PROJECT SUMMARY Cognitive damage induced by anesthesia delivered in the course of surgery and other clinical procedures has been the focus of increasing attention in recent years. A growing body of literature has established that anesthesia can potentially lead to pathological effects including increased apoptosis and disruption of myelin formation, ultimately resulting in learning deficiencies. However, the mechanisms underlying these anesthesia-induced changes are not well understood. We have reported previously that isoflurane anesthesia significantly increases the oxygen level in brain tissue compared to the awake state. Oxidative stress is a well- established source of neurotoxicity which is known to induce neuronal and glial cell death and can disrupt myelin formation. Brain hyperoxia could therefore play a key role in explaining the learning impairments associated with anesthesia. The proposed study will examine the relationship between anesthesia, brain oxygen level, and structural, biochemical, and behavioral measures of pathology. In Aim 1, we will characterize oxygen, electrophysiological responses, and reactive oxygen species under two common inhaled anesthetics (isoflurane and sevoflurane,) in air and in 80% oxygen. In Aim 2, we will evaluate the effect of anesthesia exposure on behavioral learning. In Aim 3, we will evaluate the structural and biochemical changes in brain induced by anesthesia exposure. These studies will provide a deeper understanding of the physiology of anesthesia and its relationship with oxygen levels in the brain. Behavioral, MRI, oxygen, and electrophysiological measurements will provide information on the short- and long-term influence of anesthesia/hyperoxia on brain structure and cognition.